Infection with Chlamydia trachomatis is responsible for significant morbidity and healthcare costs throughout the world. Work from our lab has demonstrated that T cells are a key mediator of immune protection against C. trachomatis. Our long-term goal has been to gain an understanding of how CD8+ T cells are stimulated in response to C. trachomatis infection. The reagents we developed in the previous funding period have allowed us to use contemporary approaches in cellular immunology to define how Chlamydia- specific T cells respond to infection. We have shown that transfer of cultured Chlamydia-specific CD8+ T cells into mice can protect against infection, yet surprisingly, a protective CD8+ T cell memory response is not stimulated following natural infection of mice or people. The apparent failure of the adaptive immune system to effectively clear the organism and/or prevent repeat infection is a hallmark of human infection with C. trachomatis, resulting in sequelae of infection such as permanent reproductive tract damage. Consistent with the findings in humans, we have observed that CD8+ T cells respond extremely well to primary infection, yet the memory cells that result from initial infection are impaired in their capacity to robustly respond to subsequent encounters with the organism. Here, our goal is to 1) understand the mechanism by which CD8+ T memory is inhibited during infection and develop methods to overcome it, and 2) identify vaccine formulations that stimulate protective CD8+ T cells and test their capacity to enhance vaccine-mediated CD4+ T cellimmunity. The vaccine strategies we will use build on a successful experimental approach using nanoparticles encapsulating an adjuvant and bound to whole inactivated organisms. Ultimately we anticipate this work will drive selection of appropriate strategies for vaccine development that provide robust protection against C. trachomatis.

Public Health Relevance

After an initial infection with most pathogens, the immune system provides protection against re-infection with the same pathogen. However, infection of the human female reproductive tract with Chlamydia trachomatis provides limited protection against reinfection, and reoccurring infections can cause permanent damage and infertility. The goal of this proposal is to 1) determine why the cells of the immune system fail to provide protection against C. trachomatis, and 2) reprogram these faulty cells using new vaccine approaches to provide protection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039558-22
Application #
9532022
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Vincent, Leah Rebecca
Project Start
1996-07-01
Project End
2021-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
22
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
Lijek, Rebeccah S; Helble, Jennifer D; Olive, Andrew J et al. (2018) Pathology after Chlamydia trachomatis infection is driven by nonprotective immune cells that are distinct from protective populations. Proc Natl Acad Sci U S A 115:2216-2221
Laborde, Rady J; Sanchez-Ferras, Oraly; Luzardo, María C et al. (2017) Novel Adjuvant Based on the Pore-Forming Protein Sticholysin II Encapsulated into Liposomes Effectively Enhances the Antigen-Specific CTL-Mediated Immune Response. J Immunol 198:2772-2784
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Zhang, Xuqing; Starnbach, Michael N (2015) An Excess of the Proinflammatory Cytokines IFN-? and IL-12 Impairs the Development of the Memory CD8+ T Cell Response to Chlamydia trachomatis. J Immunol 195:1665-75
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Stary, Georg; Olive, Andrew; Radovic-Moreno, Aleksandar F et al. (2015) VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells. Science 348:aaa8205
Fankhauser, Sarah C; Starnbach, Michael N (2014) PD-L1 limits the mucosal CD8+ T cell response to Chlamydia trachomatis. J Immunol 192:1079-90
Davila, Sergio J; Olive, Andrew J; Starnbach, Michael N (2014) Integrin ?4?1 is necessary for CD4+ T cell-mediated protection against genital Chlamydia trachomatis infection. J Immunol 192:4284-93
Olive, Andrew J; Haff, Madeleine G; Emanuele, Michael J et al. (2014) Chlamydia trachomatis-induced alterations in the host cell proteome are required for intracellular growth. Cell Host Microbe 15:113-24

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